Testosterone: therapeutic or toxic for the cardiovascular health of men?
Authors: Erin D Michos, Matthew J Budoff
Journal: The Lancet Healthy Longevity (2022)

Sex differences in the risk of cardiovascular disease have been attributed to differences in sex hormone concentrations between men and women. In pre-menopausal women, endogenous oestrogens are thought to confer a protective effect on the vasculature in delaying the onset of cardiovascular disease (ie, the so-called female advantage). Conversely a more androgenic (so-called male-like) sex hormone pattern in pre-menopausal women (such as those with polycystic ovary syndrome)1Osibogun O Ogunmoroti O Michos ED Polycystic ovary syndrome and cardiometabolic risk: Opportunities for cardiovascular disease prevention.Trends Cardiovasc Med. 2020; 30: 399-404Crossref PubMed Scopus (73) Google Scholar and in post-menopausal women2Zhao D Guallar E Ouyang P et al.Endogenous sex hormones and incident cardiovascular disease in post-menopausal women.J Am Coll Cardiol. 2018; 71: 2555-2566Crossref PubMed Scopus (155) Google Scholar has been associated with increased cardiovascular risk. Therefore, it has been speculated that higher testosterone concentrations in men might account for some of their increased age-adjusted cardiovascular event rates compared with women. The overall question: is testosterone beneficial or harmful to men's cardiovascular health?Bioavailable testosterone concentrations progressively decline in men with advancing age at a rate of about 2% per year.3Feldman HA Longcope C Derby CA et al.Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.J Clin Endocrinol Metab. 2002; 87: 589-598Crossref PubMed Scopus (1028) Google Scholar This age-related decline has been referred to as "andropause" or "male menopause". In epidemiologic studies, a low concentration of endogenous testosterone is associated with cardiovascular risk in men.4Maggio M Basaria S Welcoming low testosterone as a cardiovascular risk factor.Int J Impot Res. 2009; 21: 261-264Crossref PubMed Scopus (57) Google Scholar Low testosterone concentrations have been implicated in a myriad of adverse cardiometabolic effects such as inflammation, insulin resistance, dyslipidemia, and atherosclerosis.4Maggio M Basaria S Welcoming low testosterone as a cardiovascular risk factor.Int J Impot Res. 2009; 21: 261-264Crossref PubMed Scopus (57) Google ScholarTestosterone replacement therapy has been used to increase libido; improve erectile dysfunction; and boost energy levels, mood, and muscle strength. Nevertheless, several5Vigen R O'Donnell CI Barón AE et al.Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.JAMA. 2013; 310: 1829-1836Crossref PubMed Scopus (716) Google Scholar, 6Basaria S Coviello AD Travison TG et al.Adverse events associated with testosterone administration.N Engl J Med. 2010; 363: 109-122Crossref PubMed Scopus (1122) Google Scholar, 7Budoff MJ Ellenberg SS Lewis CE et al.Testosterone treatment and coronary artery plaque volume in older men with low testosterone.JAMA. 2017; 317: 708-716Crossref PubMed Scopus (225) Google Scholar (but not all8Fernández-Balsells MM Murad MH Lane M et al.Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.J Clin Endocrinol Metab. 2010; 95: 2560-2575Crossref PubMed Scopus (553) Google Scholar) observational and clinical trial studies have suggested a possible increased cardiovascular risk from testosterone replacement therapy when given to older men. Additionally, Mendelian randomisation studies have indicated that genetically predicted higher testosterone concentrations are associated with increased risk of heart failure in men.9Luo S Au Yeung SL Zhao JV Burgess S Schooling CM Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: Mendelian randomisation study in UK Biobank.BMJ. 2019; 364: l476Crossref PubMed Scopus (47) Google Scholar In 2014, the US Food and Drug Administration issued a warning cautioning against using testosterone replacement therapy for aging-related low testosterone due to possible increased cardiovascular risks; it was recommended to reserve this type of therapy for symptomatic hypogonadism. The data remain inconclusive, and many men with hypogonadism who might benefit from testosterone replacement therapy could be unnecessarily deterred from this potentially helpful therapy.To help shed light on this clinical dilemma, in this issue of The Lancet Healthy Longevity, Jemma Hudson and colleagues10Hudson J Cruickshank M Quinton R et al.Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.Lancet Healthy Longev. 2022; 3: e381-e393Summary Full Text Full Text PDF Scopus (4) Google Scholar did a meta-analysis of 35 placebo-controlled trials of testosterone replacement therapy that included 5601 men with low baseline testosterone concentrations (≤12 nmol/L [350 ng/dL]) and 17 of these trials had individual patient-level data available. The mean duration of treatment was 9·5 months. However, during this short-term follow-up, reassuringly, there was no significantly increased risk of cardiovascular events between the testosterone replacement therapy group and placebo groups (odds ratio 1·07 [95% CI 0·81–1·42]; p=0·62). Furthermore, there was no particular subgroup identified at significantly increased risk for cardiovascular events with testosterone replacement therapy. The average age of participants in the trials was 65 years (SD 11), and about 8% of participants had a history of myocardial infarction. However, there was no evidence for treatment interaction by baseline cardiovascular status or age.First, congratulations to the authors for performing the largest individual-level analysis of testosterone trials to date. The authors were able to investigate the relationship of testosterone replacement therapy with multiple subtypes of cardiovascular disease and non-cardiovascular outcomes, as well as changes in several physiological markers (ie, glycaemia, blood pressure, haematocrit, and lipids). Although the authors report significant reductions in total cholesterol, high-density lipoprotein cholesterol, and triglycerides with testosterone replacement therapy, it should be acknowledged that these changes were rather modest—for example, only a 3% difference in low-density lipoprotein cholesterol concentrations was observed.Although their analysis is reassuring for safety, meta-analyses are only as good as the underlying data available. Unfortunately, the data are still too insufficient to make conclusions on outcomes because the follow-up period was too short. The duration ranged from 3 months to 3 years in the trials and results were not changed by including follow-up time in the models, but there was little evidence to support cardiovascular safety beyond a 12-month duration. Future trials will require longer follow-up.There is an on-going cardiovascular outcome trial for testosterone replacement therapy—the TRAVERSE trial (NCT03518034). This trial enrolled 5246 men between ages 45–80 years with low serum testosterone concentrations (<300 ng/dL) who have at least one sign or symptom of hypogonadism and either have established cardiovascular risk or are at high risk for cardiovascular disease. Participants were randomly assigned to receive testosterone gel or placebo, and the primary outcome is a major adverse cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) at 60 months. The trial began in 2018 is anticipated to finish in late 2022.In summary, we should wait for the results of TRAVERSE to be published before widespread use of testosterone replacement therapy is considered. Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the Testosterone Trials7Budoff MJ Ellenberg SS Lewis CE et al.Testosterone treatment and coronary artery plaque volume in older men with low testosterone.JAMA. 2017; 317: 708-716Crossref PubMed Scopus (225) Google Scholar and the excess cardiovascular events observed in the TOM trial.6Basaria S Coviello AD Travison TG et al.Adverse events associated with testosterone administration.N Engl J Med. 2010; 363: 109-122Crossref PubMed Scopus (1122) Google Scholar At this time, hormone therapy should still be used selectively, paying attention to cardiovascular risk profile in individuals.This online publication has been corrected. The corrected version first appeared at thelancet.com/healthy-longevity on June 10, 2022 Sex differences in the risk of cardiovascular disease have been attributed to differences in sex hormone concentrations between men and women. In pre-menopausal women, endogenous oestrogens are thought to confer a protective effect on the vasculature in delaying the onset of cardiovascular disease (ie, the so-called female advantage). Conversely a more androgenic (so-called male-like) sex hormone pattern in pre-menopausal women (such as those with polycystic ovary syndrome)1Osibogun O Ogunmoroti O Michos ED Polycystic ovary syndrome and cardiometabolic risk: Opportunities for cardiovascular disease prevention.Trends Cardiovasc Med. 2020; 30: 399-404Crossref PubMed Scopus (73) Google Scholar and in post-menopausal women2Zhao D Guallar E Ouyang P et al.Endogenous sex hormones and incident cardiovascular disease in post-menopausal women.J Am Coll Cardiol. 2018; 71: 2555-2566Crossref PubMed Scopus (155) Google Scholar has been associated with increased cardiovascular risk. Therefore, it has been speculated that higher testosterone concentrations in men might account for some of their increased age-adjusted cardiovascular event rates compared with women. The overall question: is testosterone beneficial or harmful to men's cardiovascular health? Bioavailable testosterone concentrations progressively decline in men with advancing age at a rate of about 2% per year.3Feldman HA Longcope C Derby CA et al.Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.J Clin Endocrinol Metab. 2002; 87: 589-598Crossref PubMed Scopus (1028) Google Scholar This age-related decline has been referred to as "andropause" or "male menopause". In epidemiologic studies, a low concentration of endogenous testosterone is associated with cardiovascular risk in men.4Maggio M Basaria S Welcoming low testosterone as a cardiovascular risk factor.Int J Impot Res. 2009; 21: 261-264Crossref PubMed Scopus (57) Google Scholar Low testosterone concentrations have been implicated in a myriad of adverse cardiometabolic effects such as inflammation, insulin resistance, dyslipidemia, and atherosclerosis.4Maggio M Basaria S Welcoming low testosterone as a cardiovascular risk factor.Int J Impot Res. 2009; 21: 261-264Crossref PubMed Scopus (57) Google Scholar Testosterone replacement therapy has been used to increase libido; improve erectile dysfunction; and boost energy levels, mood, and muscle strength. Nevertheless, several5Vigen R O'Donnell CI Barón AE et al.Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.JAMA. 2013; 310: 1829-1836Crossref PubMed Scopus (716) Google Scholar, 6Basaria S Coviello AD Travison TG et al.Adverse events associated with testosterone administration.N Engl J Med. 2010; 363: 109-122Crossref PubMed Scopus (1122) Google Scholar, 7Budoff MJ Ellenberg SS Lewis CE et al.Testosterone treatment and coronary artery plaque volume in older men with low testosterone.JAMA. 2017; 317: 708-716Crossref PubMed Scopus (225) Google Scholar (but not all8Fernández-Balsells MM Murad MH Lane M et al.Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.J Clin Endocrinol Metab. 2010; 95: 2560-2575Crossref PubMed Scopus (553) Google Scholar) observational and clinical trial studies have suggested a possible increased cardiovascular risk from testosterone replacement therapy when given to older men. Additionally, Mendelian randomisation studies have indicated that genetically predicted higher testosterone concentrations are associated with increased risk of heart failure in men.9Luo S Au Yeung SL Zhao JV Burgess S Schooling CM Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: Mendelian randomisation study in UK Biobank.BMJ. 2019; 364: l476Crossref PubMed Scopus (47) Google Scholar In 2014, the US Food and Drug Administration issued a warning cautioning against using testosterone replacement therapy for aging-related low testosterone due to possible increased cardiovascular risks; it was recommended to reserve this type of therapy for symptomatic hypogonadism. The data remain inconclusive, and many men with hypogonadism who might benefit from testosterone replacement therapy could be unnecessarily deterred from this potentially helpful therapy. To help shed light on this clinical dilemma, in this issue of The Lancet Healthy Longevity, Jemma Hudson and colleagues10Hudson J Cruickshank M Quinton R et al.Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.Lancet Healthy Longev. 2022; 3: e381-e393Summary Full Text Full Text PDF Scopus (4) Google Scholar did a meta-analysis of 35 placebo-controlled trials of testosterone replacement therapy that included 5601 men with low baseline testosterone concentrations (≤12 nmol/L [350 ng/dL]) and 17 of these trials had individual patient-level data available. The mean duration of treatment was 9·5 months. However, during this short-term follow-up, reassuringly, there was no significantly increased risk of cardiovascular events between the testosterone replacement therapy group and placebo groups (odds ratio 1·07 [95% CI 0·81–1·42]; p=0·62). Furthermore, there was no particular subgroup identified at significantly increased risk for cardiovascular events with testosterone replacement therapy. The average age of participants in the trials was 65 years (SD 11), and about 8% of participants had a history of myocardial infarction. However, there was no evidence for treatment interaction by baseline cardiovascular status or age. First, congratulations to the authors for performing the largest individual-level analysis of testosterone trials to date. The authors were able to investigate the relationship of testosterone replacement therapy with multiple subtypes of cardiovascular disease and non-cardiovascular outcomes, as well as changes in several physiological markers (ie, glycaemia, blood pressure, haematocrit, and lipids). Although the authors report significant reductions in total cholesterol, high-density lipoprotein cholesterol, and triglycerides with testosterone replacement therapy, it should be acknowledged that these changes were rather modest—for example, only a 3% difference in low-density lipoprotein cholesterol concentrations was observed. Although their analysis is reassuring for safety, meta-analyses are only as good as the underlying data available. Unfortunately, the data are still too insufficient to make conclusions on outcomes because the follow-up period was too short. The duration ranged from 3 months to 3 years in the trials and results were not changed by including follow-up time in the models, but there was little evidence to support cardiovascular safety beyond a 12-month duration. Future trials will require longer follow-up. There is an on-going cardiovascular outcome trial for testosterone replacement therapy—the TRAVERSE trial (NCT03518034). This trial enrolled 5246 men between ages 45–80 years with low serum testosterone concentrations (<300 ng/dL) who have at least one sign or symptom of hypogonadism and either have established cardiovascular risk or are at high risk for cardiovascular disease. Participants were randomly assigned to receive testosterone gel or placebo, and the primary outcome is a major adverse cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) at 60 months. The trial began in 2018 is anticipated to finish in late 2022. In summary, we should wait for the results of TRAVERSE to be published before widespread use of testosterone replacement therapy is considered. Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the Testosterone Trials7Budoff MJ Ellenberg SS Lewis CE et al.Testosterone treatment and coronary artery plaque volume in older men with low testosterone.JAMA. 2017; 317: 708-716Crossref PubMed Scopus (225) Google Scholar and the excess cardiovascular events observed in the TOM trial.6Basaria S Coviello AD Travison TG et al.Adverse events associated with testosterone administration.N Engl J Med. 2010; 363: 109-122Crossref PubMed Scopus (1122) Google Scholar At this time, hormone therapy should still be used selectively, paying attention to cardiovascular risk profile in individuals. This online publication has been corrected. The corrected version first appeared at thelancet.com/healthy-longevity on June 10, 2022 This online publication has been corrected. The corrected version first appeared at thelancet.com/healthy-longevity on June 10, 2022 This online publication has been corrected. The corrected version first appeared at thelancet.com/healthy-longevity on June 10, 2022 EDM is supported by the Amato Fund in Women's Cardiovascular Health at Johns Hopkins School of Medicine. EDM served on a Medical Advisory Board for Novartis, Esperion, Amarin, and Astra Zeneca outside of the submitted work. MJB receives grant support from General Electric. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysisWe found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Full-Text PDF Open AccessCorrection to Lancet Healthy Longev 2022; 3: e368–69Erin D Michos, Matthew J Budoff. Testosterone: therapeutic or toxic for the cardiovascular health of men? Lancet Healthy Longev 2022; 3: e368–69—In this Comment a change has been made as follows: The duration ranged from 3 months to 3 years in the trials and results were not changed by including follow-up time in the models, but there was little evidence to support cardiovascular safety beyond a 12-month duration. This correction has been made as of June 10, 2022. Full-Text PDF Open Access